Arteriogenesis by Ultrasonic Microbubble Destruction

通过超声波微泡破坏进行动脉生成

• 批准号: 7141474
• 负责人: Richard J. Price
• 金额: $ 36.04万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7141474
• 关键词: angiogenesis; arterioles; artery occlusion; bioimaging /biomedical imaging; cardiovascular imaging /visualization; cell proliferation; contrast media; dosage; fibroblast growth factor; gene delivery system; genetically modified animals; hematopoietic stem cells; laboratory mouse; laboratory rat; microcapsule; microcirculation; monocyte chemoattractant protein 1; musculoskeletal circulation; nanomedicine; polyethylenes; reactive hyperemia; sectioning; striated muscles; transfection; ultrasound therapy; vascular smooth muscle

DESCRIPTION (provided by applicant): The targeted stimulation of arteriogenesis, which is defined as the formation and lumenal expansion of the arterioles and arteries, is a promising treatment for ischemia caused by occlusive vascular disease. To date, attempts at creating therapeutic arteriogenesis have centered on the delivery of selected growth factor genes and proteins: Recently, we have developed an innovative new technique, based on contrast agent microbubble destruction with ultrasound, for stimulating arteriogenesis in and around regions of ischemia. This arteriogenic response, which may be targeted to selected tissue regions using the ultrasound beam, is accompanied by an increase in hyperemic capacity in the treated tissue, thereby demonstrating the potential of this technique for restoring blood flow to organs affected by arterial occlusion. In the clinical setting, this method has the potential to be performed with minimal invasiveness. This proposal consists of 4 specific aims that broadly address the clinical potential of the ultrasound- microbubble technique for enhancing blood flow and the rational manipulation of the technique for amplifying and potentially prolonging arteriogenesis. The first and second specific aims will respectively test the efficacy of ultrasonic microbubble destruction for enhancing blood flow to muscle that is chronically affected by vascular occlusion and establish which microvascular remodeling events create the flow enhancement. Studies for the third specific aim will determine how arteriogenesis and flow restoration can be controlled through alterations in user-controlled factors, namely microbubble size, microbubble dosage, ultrasound frequency, and application time. With this information, we will then develop an optimized protocol for generating arteriogenesis at a clinically relevant microbubble dosage. In the fourth specific aim, we will deliver polyethylenimine (PEI) nanocomplexes bearing genes for either a pro-arteriogenic growth factor (bFGF) or a pro-arteriogenic cytokine (MCP-1) to the arterially occluded muscle. These final studies will combine a state-of-the-art approach for cell transfection with an ultrasound targeted delivery strategy, with the goal of rationally manipulating the magnitude and longevity of the arteriogenesis response. Given the broad applicability of this targeted gene delivery method, it is likely these studies will have a significant impact on the investigation and treatment of many other pathologies and conditions.

描述（由申请人提供）：动脉生成的靶向刺激，其定义为小动脉和动脉的形成和管腔扩张，是治疗闭塞性血管疾病引起的缺血的有前途的治疗方法。迄今为止，创造治疗性动脉生成的尝试主要集中在输送选定的生长因子基因和蛋白质上：最近，我们开发了一种创新的新技术，基于超声波破坏造影剂微泡，用于刺激缺血区域及其周围的动脉生成。这种动脉生成反应可以使用超声波束针对选定的组织区域，伴随着治疗组织充血能力的增加，从而证明了该技术恢复受动脉闭塞影响的器官血流的潜力。在临床环境中，该方法有可能以微创方式进行。该提案包括 4 个具体目标，广泛解决超声微泡技术增强血流的临床潜力以及合理操作该技术以放大和潜在延长动脉生成的问题。第一个和第二个具体目标将分别测试超声微泡破坏对于增强流向长期受血管闭塞影响的肌肉的血流的功效，并确定哪些微血管重塑事件导致血流增强。针对第三个具体目标的研究将确定如何通过改变用户控制的因素（即微泡大小、微泡剂量、超声频率和应用时间）来控制动脉生成和血流恢复。有了这些信息，我们将开发一个优化的方案，以临床相关的微泡剂量产生动脉生成。在第四个具体目标中，我们将向动脉闭塞的肌肉递送带有促动脉生长因子（bFGF）或促动脉细胞因子（MCP-1）基因的聚乙烯亚胺（PEI）纳米复合物。这些最终研究将把最先进的细胞转染方法与超声靶向递送策略相结合，目标是合理控制动脉生成反应的程度和寿命。鉴于这种靶向基因传递方法的广泛适用性，这些研究可能会对许多其他病理和病症的调查和治疗产生重大影响。